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Abstract:

There is provided a film coated pharmaceutical composition comprising
5'-deoxy-5-fluoro-N-[(pentyloxy)-carbonyl]-cytidine (capecitabine) and at
least one disintegrant selected from the group comprising of crospovidone
(particle size <15-400μ), croscarmellose sodium, sodium starch
glycolate, low-substituted hydroxypropylcellulose, Pharmaburst C or any
combination of these, together with other pharmaceutically acceptable
excipients to form a rapidly disintegrating tablet. This tablet
disintegrates in water at 37° C. in a USP Disintegration Apparatus
in less than 2 minutes, preferably 1 minute and have a hardness of 8-13
strong Cobb-Units.

Claims:

1. A film coated pharmaceutical composition comprising capecitabine and
at least one disintegrant, said composition disintegrating in water at
37.degree. C. in a USP Disintegration Apparatus in less than 2 minutes
and having a hardness of 8-13 strong Cobb-Units.

2. The composition of claim 1 in which capecitabine, based upon the total
weight of the kernel composition, comprises from about 10% to about 50%.

3. The composition of claim 2 comprising from about 50 mg to about 1500
mg of capecitabine.

4. The composition of claim 3 comprising from about 100 mg to about 750
mg of capecitabine.

6. The pharmaceutical composition of claim 1, wherein at least one
disintegrant is selected from the group consisting of crospovidone having
a particle size in the range of 90% less than 15 microns to a particle
size in the range of 90% less than 400 microns, croscarmellose sodium,
sodium starch glycolate, low-substituted hydroxypropylcellulose,
Pharmaburst C or any combination of said disintegrants.

7. The composition of claim 5 in which the disintegrant is from about 10
to about 50% per unit dosage form.

8. The composition of claim 6 wherein the disintegrant is from about 20%
to about 40% per unit dosage form.

9. The composition of claim 7 wherein the disintegrant is about 30% per
unit dosage form.

10. The pharmaceutical composition of claim 1 which contains in addition
a directly compressible polyhydric alcohol.

11. The composition of claim 9 wherein the alcohol is mannitol and
comprises from about 2% to about 25% per unit dosage form.

12. The composition of claim 10 wherein the mannitol comprises about 4%
to about 20% per unit dosage form.

13. The composition of claim 11 wherein the mannitol comprises about 6%
to about 16% per unit dosage form.

14. The pharmaceutical composition of claim 1 which contains from about
4% to about 30% microcrystalline cellulose per unit dosage form.

15. The composition of claim 13 which contains from about 8% to about 25%
microcrystalline cellulose per unit dosage form.

16. The composition of claim 14 which contains about 12% to about 22%
microcrystalline cellulose per unit dosage form.

17. The composition of claim 1 wherein the pharmaceutical composition
disintegrates in less than 1 minute.

18. The composition of claim 1 which contains a binder selected from the
group consisting of hydroxypropyl methylcellulose,
hydroxypropylcellulose, povidone, pregelatinized starch and cold swelling
corn starch.

19. The composition of claim 17 wherein capecitabine comprises from about
50 mg to about 1500 mg per unit dosage form.

20. The composition of claim 19 wherein capecitabine comprises from about
100 mg to about 750 mg per unit dosage form.

22. A pharmaceutical composition which disintegrates in water at
37.degree. C. in a USP Disintegration Apparatus in less than 1 minute
comprising capecitabine, at least one disintegrant, a binder, at least
one filler, a lubricant, at least one sweetening agent and at least one
flavorant.

29. A film coated pharmaceutical composition which disintegrates in water
at 37.degree. C. in a USP Disintegration Apparatus in less than 2 minutes
comprising 125.00 mg of Capecitabine, 3.57 mg of Hypromellose, 37.50 mg
of Crospovidone, 89.30 mg of Pharmaburst C, 58.93 mg of Mannitol, 46.82
mg of Microcrystalline Cellulose, 8.22 mg of Magnesium Stearate, 15.54 mg
of Aspartame, 3.22 mg of Saccharin Sodium, 7.86 mg of Vanillin, 1.47 mg
of Bittermasking Blend and 2.97 mg of Strawberry Flavor.

30. A film coated pharmaceutical composition which disintegrates in water
at 37.degree. C. in a USP Disintegration Apparatus in less than 2 minutes
comprising 150.00 mg of Capecitabine, 4.28 mg of Hypromellose, 45.00 mg
of Crospovidone, 107.16 mg of Pharmaburst C, 70.75 mg of Mannitol, 56.18
mg of Microcrystalline Cellulose, 9.86 mg of Magnesium Stearate, 18.64 mg
of Aspartame, 3.86 mg of Saccharin Sodium, 9.43 mg of Vanillin, 1.76 mg
of Bittermasking Blend and 3.56 mg of Strawberry Flavor.

31. A film coated pharmaceutical composition which disintegrates in water
at 37.degree. C. in a USP Disintegration Apparatus in less than 2 minutes
comprising 175.00 mg of Capecitabine, 5.00 mg of Hypromellose, 52.50 mg
of Crospovidone, 125.00 mg of Pharmaburst C, 82.56 mg of Mannitol, 65.54
mg of Microcrystalline Cellulose, 11.50 mg of Magnesium Stearate, 21.75
mg of Aspartame, 4.50 mg of Saccharin Sodium, 11.00 mg of Vanillin, 2.06
mg of Bittermasking Blend and 4.15 mg of Strawberry Flavor.

32. A film coated pharmaceutical composition which disintegrates in water
at 37.degree. C. in a USP Disintegration Apparatus in less than 2 minutes
comprising 250.00 mg of Capecitabine, 7.14 mg of Hypromellose, 75.00 mg
of Crospovidone, 178.60 mg of Pharmaburst C, 117.92 mg of Mannitol, 93.63
mg of Microcrystalline Cellulose, 16.43 mg of Magnesium Stearate, 31.07
mg of Aspartame, 6.43 mg of Saccharin Sodium, 15.71 mg of Vanillin, 2.94
mg of Bittermasking Blend and 5.93 mg of Strawberry Flavor.

33. A film coated pharmaceutical composition which disintegrates in water
at 37.degree. C. in a USP Disintegration Apparatus in less than 2 minutes
comprising 350.00 mg of Capecitabine, 10.00 mg of Hypromellose, 105.00 mg
of Crospovidone, 250.00 mg of Pharmaburst C, 165.12 mg of Mannitol,
131.08 mg of Microcrystalline Cellulose, 23.00 mg of Magnesium Stearate,
43.50 mg of Aspartame, 9.00 mg of Saccharin Sodium, 22.00 mg of Vanillin,
4.12 mg of Bittermasking Blend and 8.30 mg of Strawberry Flavor.

34. A film coated pharmaceutical composition which disintegrates in water
at 37.degree. C. in a USP Disintegration Apparatus in less than 2 minutes
comprising 500.00 mg of Capecitabine, 14.28 mg of Hypromellose, 150.00 mg
of Crospovidone, 357.20 mg of Pharmaburst C, 235.72 mg of Mannitol,
187.28 mg of Microcrystalline Cellulose, 32.88 mg of Magnesium Stearate,
62.16 mg of Aspartame, 12.88 mg of Saccharin Sodium, 31.44 mg of
Vanillin, 5.88 mg of Bittermasking Blend and 11.88 mg of Strawberry
Flavor.

35. A film coated pharmaceutical composition which disintegrates in water
at 37.degree. C. in a USP Disintegration Apparatus in less than 2 minutes
comprising 125.00 mg of Capecitabine, 3.57 mg of Hypromellose, 62.50 mg
of Crospovidone, 58.93 mg of Mannitol, 82.26 mg of Microcrystalline
Cellulose, 7.41 mg of Magnesium Stearate, 15.54 mg of Aspartame, 3.22 mg
of Saccharin Sodium, 7.86 mg of Vanillin, 1.47 mg of Bittermasking Blend
and 2.97 mg of Strawberry Flavor.

36. A film coated pharmaceutical composition which disintegrates in water
at 37.degree. C. in a USP Disintegration Apparatus in less than 2 minutes
comprising 150.00 mg of Capecitabine, 4.28 mg of Hypromellose, 75.01 mg
of Crospovidone, 70.75 mg of Mannitol, 98.71 mg of Microcrystalline
Cellulose, 8.90 mg of Magnesium Stearate, 18.64 mg of Aspartame, 3.86 mg
of Saccharin Sodium, 9.43 mg of Vanillin, 1.76 mg of Bittermasking Blend
and 3.56 mg of Strawberry Flavor.

37. A film coated pharmaceutical composition which disintegrates in water
at 37.degree. C. in a USP Disintegration Apparatus in less than 2 minutes
comprising 175.00 mg of Capecitabine, 5.00 mg of Hypromellose, 87.50 mg
of Crospovidone, 82.50 mg of Mannitol, 115.16 mg of Microcrystalline
Cellulose, 10.37 mg of Magnesium Stearate, 21.76 mg of Aspartame, 4.50 mg
of Saccharin Sodium, 11.00 mg of Vanillin, 2.06 mg of Bittermasking Blend
and 4.15 mg of Strawberry Flavor.

38. A pharmaceutical composition which disintegrates in water at
37.degree. C. in a USP Disintegration Apparatus in less than 2 minutes
comprising 250.00 mg of Capecitabine, 7.14 mg of Hypromellose, 125.00 mg
of Crospovidone, 117.86 mg of Mannitol, 164.52 mg of Microcrystalline
Cellulose, 14.82 mg of Magnesium Stearate, 31.08 mg of Aspartame, 6.44 mg
of Saccharin Sodium, 15.72 mg of Vanillin, 2.94 mg of Bittermasking Blend
and 5.94 mg of Strawberry Flavor.

39. A film coated pharmaceutical composition which disintegrates in water
at 37.degree. C. in a USP Disintegration Apparatus in less than 2 minutes
comprising 350.00 mg of Capecitabine, 10.00 mg of Hypromellose, 175.00 mg
of Crospovidone, 165.00 mg of Mannitol, 230.32 mg of Microcrystalline
Cellulose, 20.74 mg of Magnesium Stearate, 43.52 mg of Aspartame, 9.00 mg
of Saccharin Sodium, 22.00 mg of Vanillin, 4.12 mg of Bittermasking Blend
and 8.30 mg of Strawberry Flavor.

40. A film coated pharmaceutical composition which disintegrates in water
at 37.degree. C. in a USP Disintegration Apparatus in less than 2 minutes
comprising 500.00 mg of Capecitabine, 14.28 mg of Hypromellose, 250.00 mg
of Crospovidone, 235.72 mg of Mannitol, 329.04 mg of Microcrystalline
Cellulose, 29.64 mg of Magnesium Stearate, 62.16 mg of Aspartame, 12.88
mg of Saccharin Sodium, 31.44 mg of Vanillin, 5.88 mg of Bittermasking
Blend and 11.88 mg of Strawberry Flavor.

Description:

FIELD OF THE INVENTION

[0001] The present invention relates to a novel rapidly disintegrating
pharmaceutical dosage form having as an active ingredient
5'-deoxy-5-fluoro-N-[(pentyloxy)-carbonyl]-cytidine (capecitabine). The
new dosage form is suitable for any patient and especially for patients
who have difficulty swallowing solid oral dosage forms, including the
pediatric and geriatric populations.

BACKGROUND OF THE INVENTION

[0002] Capecitabine is a fluoropyrimidine carbamate with antineoplastic
activity. It is an orally administered systemic prodrug of
5'-deoxy-5-fluorouridine (5'-DFUR), an antineoplastic agent. Capecitabine
is marketed in the United States by Roche Laboratories under the brand
name Xeloda®. The chemical name for capecitabine is
5'-deoxy-5-fluoro-N-[(pentyloxy)-carbonyl]-cytidine and has the following
structural formula:

##STR00001##

[0003] Capecitabine is covered in US patents, including U.S. Pat. No.
4,966,891 and 5,472,949 and U.S. Ser. No. 60/667,509, filed Apr. 1, 2005.
Improved methods for the manufacture of capecitabine are taught in U.S.
Pat. Nos. 5,453,497 and 5,476,932, and application U.S. Ser. No.
60/532,266, filed Dec. 22, 2003. To the extent necessary, any and all of
the foregoing patents and applications are herein incorporated by
reference.

[0004] In the United States, Capecitabine is currently approved for the
treatment of colon and breast cancer. The currently approved/recommended
dose of capecitabine in those indications is 1250 mg/m2 administered
orally twice daily (equivalent to 2500 mg/m2 total daily dose) for
14 days followed by a 7-day rest period given as 3-week cycles, for as
long as needed. See approved package insert. Typically the mean duration
of treatment is 3 to 6 three-week cycles. The currently approved unit
dosage forms are a light peach-colored film coated tablet containing 150
mg of capecitabine and a peach-colored film coated tablet containing 500
mg of capecitabine.

[0005] As with most solid oral dosage forms, the currently marketed
capecitabine tablet may be difficult to swallow by the pediatric and
geriatric populations, as well as by patients with swallowing impediments
and blockages.

[0006] The capecitabine tablet currently on the market (Xeloda® Roche)
typically requires approximately 7-12 minutes to disintegrate in water
(USP Disintegration Test), depending on the size of the tablet.
Traditional excipients currently used in these tablets, such as lactose
and croscarmellose sodium, by themselves do not overcome the cohesive
property of capecitabine in the tablet. The end result is that the
marketed tablet slowly disintegrates by surface erosion and is thus not
very amenable to rapid dispersion or disintegration in water prior to
oral administration to swallowing-compromised patients.

[0007] A rapidly disintegrating tablet, such as one having a quickly
dispersing matrix, and more preferably a rapidly disintegrating flavored
tablet, is thus desirable to remedy the foregoing difficulty of slow
tablet erosion in water prior to oral administration.

SUMMARY OF THE INVENTION

[0008] The present invention provides a rapidly disintegrating
pharmaceutical dosage form for oral administration of
5'-deoxy-5-fluoro-N-[(pentyloxy)-carbonyl]-cytidine (capecitabine) that
is suitable for administration to patients that have difficulty
swallowing solid oral dosage forms.

DETAILED DESCRIPTION OF THE INVENTION

[0009] The present invention provides a rapidly disintegrating film coated
capecitabine pharmaceutical dosage form suitable for oral administration.
Preferably, the tablet disintegrates in water at 37° C. (USP
Disintegration Test) in less than about 2 minutes, more preferably in
less than about 1 minute, and have a hardness of about 8-13 strong
Cobb-Units (scu). By manually stirring in water at room temperature, the
tablet disintegrates in less than or equal to about 3 minutes. In a
preferred embodiment, the composition comprises, based upon the total
weight of the final unit dosage form, from about 10% to about 50%, more
preferably from about 25% to about 35%, and most preferably 30%, of
capecitabine and from about 10% to about 50%, more preferably from about
20% to about 40%, and most preferably 30%, per unit dosage form of at
least one disintegrant.

[0010] Yet another preferred embodiment of the present invention relates
to a lactose free tablet composition for lactose intolerant individuals
wherein the lactose is replaced by additional mannitol.

[0011] In addition, a directly compressible polyhydric alcohol, such as
mannitol, and a microcrystalline cellulose are essential to maintain
tablet strength without compromising the disintegration of the tablet.
The composition of mannitol comprises from about 2% to about 25%, more
preferably from about 4% to about 20% and most preferably 6% to about 16%
and the microcrystalline cellulose comprises from about 4% to about 30%,
more preferably from about 8% to about 25% and most preferably 12% to
about 22% per unit dosage form.

[0012] Preferably, the composition comprises from about 50mg to about
1500mg, preferably 100 mg to about 750 mg, and more preferably from about
125 mg to about 500 mg, of capecitabine. Most preferably, the composition
comprises, per unit dosage form, 125 mg, 150 mg, 175 mg, 250 mg ,350 mg
or 500mg of capecitabine.

[0013] Useful disintegrants include, but are not limited to, crospovidone
having a particle size in the range of 90% less than 15 microns to a
particle size in the range of 90% less than 400 microns, croscarmellose
sodium, sodium starch glycolate, low-substituted hydroxypropylcellulose,
or any commercially available disintegrant, such as Pharmaburst C®, a
mannitol/sorbitol combination disclosed and claimed in U.S. Pat. No.
7,118,765 incorporated herein by reference (available from SPI Pharma,
New Castle, Del.) or any combination thereof.

[0014] The pharmaceutical compositions of the invention may include
additional therapeutically inert inorganic or organic carriers and
excipients. For example, such compositions may include flavorants such as
vanillin, bittermasking blend, strawberry flavor or any other flavorant
or flavorant combinations which are typically added to pharmaceutical
preparations to render them palatable for oral administration.

[0015] The compositions may also include sweetening agents such as
saccharin sodium, aspartame, sucralose, acesulfame-K, and sucrose.

[0016] The compositions may also include binders such as hydroxypropyl
methylcellulose, hydroxypropylcellulose, povidone, pregelatinized starch
or any other cold swelling corn starch.

[0017] The compositions may also include fillers such as lactose anhydrous
or microcrystalline cellulose.

[0018] The compositions may also include coloring agents, coating agents,
antioxidants, stabilizers, lubricants (e.g., magnesium stearate),
granulation aids, flow aids, and such other agents and materials as are
known to those skilled in the art of making pharmaceutical dosage forms
for human oral consumption.

[0019] In an embodiment, the unit dosage form is a tablet, preferably a
film coated tablet. The coating may contain excipients such as a film
former (polymer), a plasticizer, an opacifier, pigments, colorants and
the like. The choice of such materials and the amounts to be utilized are
considered to be within the art.

[0020] The film coat composition can be selected from, for example,
Hypromellose, Polyvinyl Alcohol, Titanium Dioxide, Talc, Iron Oxide Color
without or with plasticizer, such as Polyethylene Glycol, Polysorbate 80,
or Triacetin.

[0021] The following examples illustrate embodiments of unit dosage forms
according to the present invention. In each case, the unit dosage form is
a film coated tablet.

[0040] Procedure: Similar to that for Examples 1-6, except replace Lactose
Anhydrous with Mannitol in Step 1 and remove Pharmaburst C in Step 6.

Disintegration Aspects of the Dosage Form

[0041] Following is a comparison of the disintegration times for the
rapidly disintegrating tablet of the present invention and the marketed
tablet at low and high tablet strengths. Disintegration times were
obtained using the USP Disintegration Apparatus without discs and
37° C. Water. The experimental test method and resultant
disintegration times observed were performed in accordance with the USP
Disintegration Test Method (USP 29, General Chapters, Physical Tests,
<709> which is herein incorporated by reference.

[0042] For the purposes of this test, disintegration does not imply
complete solution of the unit or even of its active constituent. Complete
disintegration is defined as that state in which any residue of the unit,
except fragments of insoluble coating or capsule shell, remaining on the
screen of the test apparatus is a soft mass having no palpably firm core.

USP Distinegration Apparatus

[0043] The apparatus consists of a basket-rack assembly, a 1000-mL,
low-form beaker, 138 to 160 mm in height and having an inside diameter of
97 to 115 mm for the immersion fluid, a thermostatic arrangement for
heating the fluid between 35 and 39, and a device for raising and
lowering the basket in the immersion fluid at a constant frequency rate
between 29 and 32 cycles per minute through a distance of not less than
53 mm and not more than 57 mm. The volume of the fluid in the vessel is
such that at the highest point of the upward stroke the wire mesh remains
at least 15 mm below the surface of the fluid and descends to not less
than 25 mm from the bottom of the vessel on the downward stroke. At no
time should the top of the basket-rack assembly become submerged. The
time required for the upward stroke is equal to the time required for the
downward stroke, and the change in stroke direction is a smooth
transition, rather than an abrupt reversal of motion. The basket-rack
assembly moves vertically along its axis. There is no appreciable
horizontal motion or movement of the axis from the vertical.

[0044] Basket-Rack Assembly--The basket-rack assembly consists of six
open-ended transparent tubes, each 77.5±2.5 mm long and having an
inside diameter of 20.7 to 23 mm and a wall 1.0 to 2.8 mm thick; the
tubes are held in a vertical position by two plates, each 88 to 92 mm in
diameter and 5 to 8.5 mm in thickness, with six holes, each 22 to 26 mm
in diameter, equidistant from the center of the plate and equally spaced
from one another. Attached to the under surface of the lower plate is a
woven stainless steel wire cloth, which has a plain square weave with
1.8- to 2.2-mm apertures and with a wire diameter of 0.57 to 0.66 mm. The
parts of the apparatus are assembled and rigidly held by means of three
bolts passing through the two plates. A suitable means is provided to
suspend the basket-rack assembly from the raising and lowering device
using a point on its axis.

[0045] The design of the basket-rack assembly may be varied somewhat,
provided the specifications for the glass tubes and the screen mesh size
are maintained.

[0046] Disks--Disks were not used.

Procedure

[0047] Uncoated or Coated Tablets--Place 1 dosage unit in each of the six
tubes of the basket. Operate the apparatus using water or the specified
medium as the immersion fluid, maintained at 37±2. At the end of the
time limit specified in the monograph, lift the basket from the fluid,
and observe the tablets to see if all of the tablets have disintegrated
completely. If 1 or 2 tablets fail to disintegrate completely, repeat the
test on 12 additional tablets. The requirement is met if not fewer than
16 of the total of 18 tablets tested are disintegrated.

[0048] Disintegration Times in Water at 37° C. (USP Disintegration
Apparatus)

[0049] As demonstrated in the above table, the capecitabine rapidly
disintegrating tablets of the invention have disintegration times in
water that are approximately eight- to thirteen-fold shorter than the
current marketed tablets at their low and high dosage strengths,
respectively.

[0050] While the invention has been illustrated by reference to specific
and preferred embodiments, those skilled in the art will understand that
variations and modifications may be made through routine experimentation
and practice of the invention. Thus, the invention is intended not to be
limited by the foregoing description, but to be defined by the appended
claims and their equivalents.